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EP1727539A1 - Utilisation de rotigotine pour traiter et prevenir le syndrome parkinson plus - Google Patents

Utilisation de rotigotine pour traiter et prevenir le syndrome parkinson plus

Info

Publication number
EP1727539A1
EP1727539A1 EP05728686A EP05728686A EP1727539A1 EP 1727539 A1 EP1727539 A1 EP 1727539A1 EP 05728686 A EP05728686 A EP 05728686A EP 05728686 A EP05728686 A EP 05728686A EP 1727539 A1 EP1727539 A1 EP 1727539A1
Authority
EP
European Patent Office
Prior art keywords
rotigotine
parkinson
use according
group
plus syndrome
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05728686A
Other languages
German (de)
English (en)
Other versions
EP1727539B1 (fr
Inventor
Dieter Scheller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCB Pharma GmbH
Original Assignee
Schwarz Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schwarz Pharma AG filed Critical Schwarz Pharma AG
Publication of EP1727539A1 publication Critical patent/EP1727539A1/fr
Application granted granted Critical
Publication of EP1727539B1 publication Critical patent/EP1727539B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • Parkinson's Plus Syndrome includes some idiopathic diseases. summarized, which are associated with the appearance of Parkinson's-like symptoms, but which can be distinguished diagnostically and clinically / pathophysiologically from Parkinson's disease.
  • Parkinson's Plus Syndrome The disease complex of Parkinson's Plus Syndrome (PPS) is assigned to multisystem atrophy (MSA), progressive supranuclear palsy (PSP), cortico-basal organ degeneration (CBGD) and dementia with Lewy Bodies (DLB).
  • MSA multisystem atrophy
  • PSP progressive supranuclear palsy
  • CBGD cortico-basal organ degeneration
  • DLB dementia with Lewy Bodies
  • Multi-system atrophies include, in particular, Sky-Drager syndrome, olivo-ponto-cerebellar atrophy (OPCA) and striatonigral degeneration (SND) (Mark et al, Neurol Clin. 2001, 19 (3): 607).
  • OPCA olivo-ponto-cerebellar atrophy
  • SND striatonigral degeneration
  • Parkinson's Plus syndrome The diseases subsumed under Parkinson's Plus syndrome are characterized by a lack of or rapidly diminishing response to L-dopa or dopamine agonists as well as additional symptoms such as cerebellar or pyramidal pathway signs, early or severe dementia as well as speech and swallowing disorders in the early phase (Mark 2001, supra; Gerlach et al, Parkinson's disease, Springer, Vienna New York, 2003).
  • Table 1 provides an overview of the differential diagnostic criteria for some Parkinson-Plus syndromes and Parkinson's disease (also known as idiopathic Parkinson's syndrome, IPS).
  • Table 1 Overview of the classification of some disease symptoms of Parkinson's-like movement disorders and differential diagnostic characteristics
  • SND striato-nigral degeneration
  • OPCA olivo-ponto-cerebellar atrophy
  • KBD cortico-basal degeneration
  • PSP progressive supranuclear gaze- '
  • IPS idiopathic Parkinson's syndrome (modified according to Mark MH, Lumping and Splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration. Neurol Clin. 2001 Aug; 19 (3) : 607-27 and Gerlach M, Reichmann H, Riederer P, Die Parkinson's disease, Springer Vienna New York, 2003).
  • Computed tomography shows.
  • Patients with IPS have a normal dopamine receptor population in SPECT except for late stage;
  • PPS patients on the other hand, show an early loss of pre- and post-synpathetic dopaminergic neurons, which is accompanied by a demonstrable reduction in the density of the dopamine receptors.
  • PET analyzes show 'a reduced L-DOPA content and L-DOPA-metabolism in IPS patients (Gerlach et al., 2003, supra).
  • Drug therapy for PPS is difficult due to the often lacking or poor response of L-Dopa and generally consists of symptomatic therapy of certain individual symptoms, e.g. therapy of hypotension.
  • Dopamine receptor agonists are usually ineffective in the treatment of PPS (Mark, 2001, supra). In exceptional cases, certain therapeutic successes with individuals Dopamine agonists have been reported, but these effects appear to be substance-specific. For example, Wenning et al (Lancet, 2004, 3, 93) report therapeutic success of bromocriptine in a study with six patients, whereas a controlled study with lisuride showed no effectiveness. Since it is known that most dopamine agonists act not only on a dopamine receptor, but have a complex receptor profile (Newman-Tancredi, J Pharmacol Exp Ther 2002, 303. 805), the cause of the effectiveness of bromocriptine in the peculiarities of the receptor profile or other substance-specific properties not further characterized.
  • Parkinson's plus syndrome is usually associated with dopaminergic neurodegeneration in the Sübstantia nigra (Mark, 2001, supra). Successful therapy can therefore be expected from the use of effective neuroprotectants that inhibit the progressive breakdown of dopaminergic neurons (Dawson and Dawson VL, Nat Neurosci. 2002 Nov: 5 SUPPI: 1058).
  • Rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphtol] is known from the prior art as a dopamine agonist and symptomatic Parkinson's disease Therapeutic known.
  • WO 02/089777 describes the transdermal administration of rotigotine in Parkinson's patients and the associated improvement in the UPDRS (Unified Parkinson's Disease Rating Scale) score, as well as various other authors (Metman et al, Clin Neuropharmacol. 2001, 24 (3 ): 163; Mucke HA, Rotigotin Schwarz Pharma. IDrugs. 2003 Sep; 6 (9): 894: The Parkinson Study Group, Arch Neurol. 2003 60 (121: 1721).
  • UPDRS Unified Parkinson's Disease Rating Scale
  • the UPDRS score is an important tool for the diagnosis and therapy of Parkinson's disease patients (Fahn S, Elton RL, Members of the UPDRS Development Committee (1987) Unified Parkinson's Disease Rating Scale. In: Fahn, S, CD Marsden, DB Calne, M Goldstein (eds) Recent Developments in Parkinson's Disease, Vol II. Mac illan Healthcare Information, Florham Park (NJ), pp 153-163, 293-304).
  • the UPDRS score only records the effect of an active ingredient on Parkinson's disease symptoms. It does not allow a direct statement about whether a Active ingredient influences the dopaminergic cell death on which the symptoms are based.
  • Parkinson-Plus Lev et al, Prog Neuropsychopharmacol Biol Psychiatry. 2003: 27 (2V.245: Michel et al, Rev Neurol (Paris). 2002: 158 Spec no 1: S24
  • various other neurodegenerative processes are said to significantly influence the development of Parkinsonism and Parkinson Plus (Hirsch et al, Ann NY Acad Sei. 2003; 991 .: 214).
  • Rotigotine previously used only for the symptomatic therapy of idiopathic Parkinson's disease has neuroprotective properties.
  • Rotigotine surprisingly shows the desired pharmacological profile in both an acute and a subacute MTPT model (Table 2, Figures 1 and 2). The results of the investigation suggest that rotigotine prevents apoptotic processes.
  • Rotigotine shows a neuroprotective effect in a mouse Parkinson's model: after acute administration of MPTP, which produces Parkinson's symptoms in humans and monkeys, the number of neurons degenerating in the acute phase was measured and the functional integrity of the striatum in the sub-acute phase by determining the density of the dopamine transporter in the terminal nerve endings.
  • rotigotine was neuroprotective: on the one hand, the number of degenerating neurons in the mesencephalon was reduced after the administration of rotigotine (Table '2) and, on the other hand, the dopaminergic innervation of the striatum was almost completely preserved or restored ( Figures 1 and 2).
  • Table 2 Number of acutely degenerating neurons in the MPTP mouse model shown with FluoroJade staining with and without treatment with a single dose of rotigotine
  • the invention therefore relates to the use of rotigotine, its salts and prodrugs as medicaments for the prevention and / or treatment of Parkinson's Plus syndrome, the term Parkinson's Plus syndrome comprising the following diseases: multisystem atrophies, progressive supranuclear palsy, corticobasal degeneration ,. Dementia with Lewy bodies, Pick's disease, hemiparkinsonism, Parkinsonism in Alzheimer's and ALS patients, and the Westphal variant of Huntington's chorea.
  • the diseases to be treated with rotigotine are preferably selected from the group of multi-system atrophies, progressive supranuclear palsy, corticobasal degeneration and diffuse Lewy body dementia.
  • Another object of the invention is a method for treating a patient with Parkinson-Plus syndrome by administering a therapeutically sufficient amount of rotigotine, its salts and / or prodrugs, or by administering a drug, the rotigotine or one of its salts and / or prodrugs contains.
  • prodrugs of rotigotine are understood to mean, in particular, compounds which are cleaved, converted or metabolized in a therapeutically effective amount to rotigotine in the human body, in particular in plasma or when penetrating through skin or mucous membrane.
  • esters e.g. Aryl carbonyl esters, alkyl carbonyl esters or cycloalkyl carbonyl esters, in particular alkyl carbonyl esters and
  • Cycloalkyl carbonyl esters each with up to 6 carbon atoms; carbonates; carbamates; acetals; ketals; acyloxyalkyl ethers; Phosphate; phosphonates; Sulfate; sulfonates; Thiocarbonylester; ⁇ xythiocarbonylester; thiocarbamates; Ether and silyl ether.
  • alkylcarbonyl ester encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group —C (O) -alkyl.
  • An alkylcarbonyl ester is formally formed from the esterification of the phenolic hydroxyl group with an alkanoic acid, for example with acetic acid, propionic acid, butyric acid, Isobutyric acid or valeric acid.
  • cycloalkylcarbonyl ester encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group —C (O) cycloalkyl.
  • aryl carbonyl ester encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group -C (O) aryl.
  • carbonates encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group —C (O) -OR.
  • carbamate includes compounds in which in each case the oxygen atom of the rotigotine to the group -C (O) -NRR1, -C (O) -NH-R1, or -C (O) -NH is bound. 2
  • acetal includes compounds in each of which x.ist the oxygen atom of the rotigotine ⁇ to the group -CH (OR) R1.
  • ketal includes compounds in which the oxygen atom of the rotigotine is bonded to the group —C (OR) R1R2.
  • acyloxyalkyl ether encompasses compounds in which each
  • Oxygen atom of the rotigotine is bound to the group -CHR-OC (O) -R1 or CH 2 -OC (O) -R1 ⁇ .
  • phosphate encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group -P (O 2 H) OR.
  • phosphonate encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group -P (O 2 H) R.
  • sulfurate encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group —S (O) 2 OR.
  • sulfonate encompasses compounds in which the oxygen atom of the rotigotine is bonded to the group —S (O) 2 R in each case.
  • ether includes compounds in which the oxygen atom of the rotigotine is bonded to the group -R.
  • R, R1, R2 are each independently selected from hydrogen, alkyl, cycloalkyl or aryl, and preferably from the group C1-6 alkyl, C3-10 cycloalkyl, and phenyl.
  • Alkyl can be a branched or unbranched alkyl group which preferably has 1 to 10 C atoms, particularly preferably 1 to 6 C atoms. Alkyl groups can additionally be substituted with one or more substituents, for example with. Halogen.
  • Cycloalkyl is an alkyl group which can only consist of pure ring-forming carbon atoms or can optionally carry further branching carbon atoms. Preferred chain lengths are 3-10, particularly preferably 4-8 or 4-6 C atoms.
  • Aryl is preferably phenyl. Phenyl may optionally be additionally substituted in one or more positions, e.g. with alkoxy, alkyl, halogen or nitro.
  • a suitable enzyme mixture is contained, for example, in the S 9 liver preparation from Gentest, Woburn, Ma, USA (embodiment 5).
  • an incubation with fresh blood or plasma or a homogenate of the subcutaneous tissue can take place in order to demonstrate a liver-independent metabolism of the prodrugs to the active component.
  • an in vitro examination of the permeation on excised skin is necessary.
  • a prodrug should release enough rotigotine to achieve a therapeutically effective steady-state concentration of rotigotine in the plasma as it does clinical or preclinical investigations are already known.
  • Effective concentrations are generally rotigotine concentrations between 0.01 and 50 ng / ml, preferably between 0.05 ng and 20 ng / ml and particularly preferably between 0.1 and 10 ng / ml plasma.
  • Rotigotine is the S (-) enantiomer of 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphtol.
  • the (R) -enantiomer is preferably present in the drug with a proportion of ⁇ 10 mol%, particularly preferably with a proportion of ⁇ 2 mol% and very particularly preferably with a molar proportion of ⁇ 1%, based on the total amount of rotigotine.
  • Rotigotine and its prodrugs can be used as free bases or in the form of the physiologically acceptable salts, e.g. in the form of the hydrochloride, in the drug.
  • Physiologically acceptable salts include non-toxic addition salts of rotigotine with organic or inorganic acids, e.g., HCI.
  • a preferred mode of administration of rotigotine is transdermal administration.
  • the dosage form can basically be selected from e.g. Ointment, paste, spray, foil, plaster or an iontophoretic device.
  • Rotigotine is preferably applied in patch form to the patient's skin, the active ingredient preferably being in a matrix of adhesive polymer, e.g. a self-adhesive polysiloxane.
  • a matrix of adhesive polymer e.g. a self-adhesive polysiloxane.
  • suitable transdermal formulations can be found in WO 99/49852, WO 02/89777, WO 02/89778, WO 04/58247, WO 04/12730, WO 04/12721 or WO 04/50083.
  • Such a dosage form enables the setting of a largely constant plasma level and thus a constant dopaminergic stimulation over the entire application interval (WO 02/89778; Metman, Clinical Neuropharmacol. 24, .2001, 163).
  • the rotigotine can be used, for example, as a salt crystal !, e.g. as a crystalline hydrochloride, suspended and injected in a hydrophobic, anhydrous medium, as described in WO 02/15903 or in the form of microcapsules,
  • Microparticles or implants based on biodegradable polymers as described for example in WO 02/38646, can be administered.
  • rotigotine and its prodrugs are transmucosal formulations, e.g. Sublingual or nasal sprays, rectal formulations or aerosols for pulmonary administration.
  • Suitable dosages of rotigotine are between 0.05 and approximately 50 mg / day, preferably daily doses between 0.1 and 40 mg and in particular between 0.2 and 20 mg / day.
  • the dosage can be creeping in, that is, the treatment can optionally start with low doses, which can then be increased to the maintenance dose.
  • the dosage interval can vary depending on the amount applied, the type of application and the daily requirement of the patient. So can a transdermal application form, for example, can be designed for once-daily, three-day or seven-day administration, while a subcutaneous or intramuscular depot can allow injections, for example, in one, two or four week intervals.
  • anti-apoptotic substances include anti-apoptotic substances (minocyclines, FK-506, cyclosporin A, zVAD) and neurotrophins, such as e.g. the glial-cell-derived neurotrophic factor (GDNF).
  • GDNF glial-cell-derived neurotrophic factor
  • a combination preparation the active ingredients used can be released largely simultaneously or else sequentially. Sequential administration can be achieved, for example, by using a dosage form, e.g. an oral tablet, two different layers with a different release profile for the different pharmaceutically active ingredients.
  • a combination preparation according to the invention comprising a rotigotine formulation can alternatively also be provided as a so-called “kit of parts”, in which the anti-apoptotic active ingredients to be administered are present in separate formulations, which are then administered simultaneously or at different times.
  • Rotiqotin patches 1.8 g of rotigotine (free base) are dissolved in 2.4 g of ethanol and added to 0.4 g of Kollidon 90F (dissolved in 1 g of ethanol).
  • This mixture is added to a 74% solution of silicone polymers (8.9 g BioPSA 7-4201 + 8.9 g BIO-PSA 7-4301 [Dow Corning]) in heptane.
  • silicone polymers 8.9 g BioPSA 7-4201 + 8.9 g BIO-PSA 7-4301 [Dow Corning]
  • After adding 2.65 g of petroleum ether the mixture is stirred at 700 rpm for 1 hour in order to obtain a homogeneous dispersion.
  • the plaster weight was finally 50 g / cm2.
  • mice For intoxication, mice are given 80 mg / kg of the neurotoxin 1-methyl-4-phenyl-1, 2,3,6-tetrahydro-pyridine (MPTP) (in portions of 20 mg / kg at two-hourly intervals, group 3-6 in Figures 1 and 2), which leads to the fact that approx. 50 - 60% of the neurons of the substantia nigra degenerate (maximum degeneration in group 3 in Figures 1 and 2).
  • Rotigotine is administered daily in doses of 0.3, 1 or 3 mg / kg over 7 days as a so-called 'slow release formulation' (see embodiment 2) (groups 4-6 in Figures 1 and 2).
  • a group of MPTP-treated animals receives rotigotine vehicle solution (see embodiment 2 without rotigotine HCL) and serves as a reference.
  • Groups 1, 2 and 7 serve as controls, with group 1 receiving no treatment, group 2 being treated with the vehicle solutions for MPTP and rotigotine, and group 7 receiving only rotigotine.
  • the animals are killed, the brains removed and frozen.
  • rotigotine is administered in doses of 0.3, 1 or 3 mg / kg as a so-called slow-release formulation (see embodiment 2). Diffusion and absorption latencies mean that rotigotine is optimally available when MPTP is given. Animals that only received vehicle solution (see Example 2 without Rotigotine HCI) serve as controls. After 24 hours, the animals are killed and the brains fixed.
  • the brain sections are stained with FluoroJade to identify degenerating cells.
  • Immunohistochemical labeling of tyrosine hydroxylase. is used to identify dopaminergic neurons.
  • the coloring of the tyrosine hydroxylase shows no differences between treated and untreated animals; FluoroJade staining shows a large number of degenerating neurons; however, the neurons have not yet been completely removed (which explains the lack of difference in tyrosine hydroxylase staining); this suggests that cell death is apoptotic and is not yet complete at the time of measurement (the apoptotic cells have not yet been completely resolved or phagocytized).
  • the number of degenerating neurons is around 50% lower after the application of rotigotine, which further demonstrates the neuroprotective property of the substance (Table 2).
  • the microsome fraction which contains the essential metabolizing enzymes is obtained from liver cell homogenates of humans, monkeys, dogs, rats or mice by differential centrifugation; alternatively, the cytoplasmic fraction can also be obtained.
  • the subcellular fraction is suspended with a buffer so that a solution with a defined protein content is obtained. After adding 1 ⁇ M of the prodrug to be tested is incubated at 37 ° C for 60 min. Then rotigotine is quantified by means of HPLC / UV or also by means of HPLC / MS and related to the amount used. For more detailed analyzes, concentration or time series are examined.

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EP05728686A 2004-03-24 2005-03-22 Utilisation de rotigotine pour traiter et prevenir le syndrome parkinson plus Expired - Lifetime EP1727539B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004014841A DE102004014841B4 (de) 2004-03-24 2004-03-24 Verwendung von Rotigotin zur Behandlung und Prävention des Parkinson-Plus-Syndroms
PCT/EP2005/003013 WO2005092331A1 (fr) 2004-03-24 2005-03-22 Utilisation de rotigotine pour traiter et prevenir le syndrome parkinson plus

Publications (2)

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EP1727539A1 true EP1727539A1 (fr) 2006-12-06
EP1727539B1 EP1727539B1 (fr) 2007-10-31

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US (1) US7872041B2 (fr)
EP (1) EP1727539B1 (fr)
JP (1) JP4801042B2 (fr)
KR (1) KR101140452B1 (fr)
CN (1) CN100581542C (fr)
AT (1) ATE376828T1 (fr)
AU (1) AU2005226911B2 (fr)
CA (1) CA2559683C (fr)
DE (2) DE102004014841B4 (fr)
EA (1) EA011278B1 (fr)
ES (1) ES2296156T3 (fr)
HK (1) HK1100765A1 (fr)
MX (1) MXPA06010747A (fr)
NO (1) NO20064792L (fr)
NZ (1) NZ550025A (fr)
UA (1) UA85583C2 (fr)
WO (1) WO2005092331A1 (fr)

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CA2559683A1 (fr) 2005-10-06
CN1960724A (zh) 2007-05-09
NZ550025A (en) 2010-07-30
US7872041B2 (en) 2011-01-18
EA200601746A1 (ru) 2007-04-27
DE102004014841B4 (de) 2006-07-06
NO20064792L (no) 2006-10-23
AU2005226911B2 (en) 2011-02-10
WO2005092331A1 (fr) 2005-10-06
DE102004014841A1 (de) 2005-10-13
JP4801042B2 (ja) 2011-10-26
ES2296156T3 (es) 2008-04-16
HK1100765A1 (en) 2007-09-28
UA85583C2 (ru) 2009-02-10
MXPA06010747A (es) 2006-12-15
US20070191470A1 (en) 2007-08-16
EA011278B1 (ru) 2009-02-27
AU2005226911A1 (en) 2005-10-06
DE502005001828D1 (de) 2007-12-13
ATE376828T1 (de) 2007-11-15
EP1727539B1 (fr) 2007-10-31
CA2559683C (fr) 2012-07-17

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